lecture 13 - new chemo targets Flashcards
What are some examples of chemotherapies (gen) and what DNA lesions do they cause?
Radiotherapy (radiation, bleomycin) - SSB, DSB, damage to bases
Mono-alkylators (temozolomide) - damage to bases, bulky adducts
Cross-linkers (N-mustards, mitomycin C, platinum drugs) - DSB, damage to bases, bulky adducts
topoisomerase inhibitors - SSB, DSB
replication inhibitors - DSB
antimetabolites (5-FU, thiopurines) - damage to bases
What strategies could we potentially target to prevent repair of the DNA-damage?
Direct inhibition of repair enzymes (MGMT, O6-benzylguanine)
inhibition of a control system (e.g. PARP1)
Checkpoint kinase, DNA-dependent protein kinases
How can O-6-methylguanine-DNA methyltransferase (MGMT) be inhibited?
Temozolomide has been trialled in combination therapies with pseudo substrates for MGMT
The substrate competes for MGMT, inhibiting the action of temozolomide
If you have resistance to over 6 alkylators, levels of MGMT can be depleted
Both O-6-benzylguanine and Patrin have been in phase I and II clinical trials - they have shown complete depletion of MGMT in a tumour
However, low doses needed as myelosuppression (depletion of bone marrow) enhanced
What is the role of PARP(-1) in the repair of damaged DNA?
PARP1 is recruited to the site of DNA damage and forms a polyADP ribose chain on the histone that is near to the site of the damage
As a result, the histone is removed from the DNA
Repair enzymes are brought to the site of damage and the site of DNA repair is fully accessible
PARG, a glycohydrolase, snips the PARP chains off and the DNA is repaired - histone returns to its place
PARP1 is therefore a clear target for modifying this process - can inhibit the repair of bases
What are some therapeutic applications of PARP1 inhibition in cancer?
Radiotherapy of cancer causes DNA strand breaks
Electrophilic cytotoxic drugs cause DNA damage
Inhibitors of topoisomerase II cause DNA single-strand breaks by inhibiting the strand re-joining step
Inhibition of PARP1 inhibits DNA repair and potentiates radiotherapy and DNA-targeted chemotherapy
What properties of simple substrate analogues are important when considering their use as inhibitors of PARP-1?
Polarity, H-bonding and size do not play a role in any variations
Electron withdrawing groups (where electron density is pulled away from the ring) is disfavoured
Electron neutral or electron favouring groups are important
Can build another ring - locking the amide in place - bulky substituent is preferred
Which treatments have been discontinued after trials?
Veliparib - inhibits PARP1 and 2, but not 3, tankyrases
Went through 1-3 clinical trials, in combination and as a single agent
What is synthetic lethality and why is it advantageous?
If a base is damaged it can lead to a single-strand break
This can be repaired by BER and SSBR, with PARP1 playing a role
If a double strand break occurs, this can lead to persistent breaks - some tumours have mutant BRCA1/2, meaning they are unable to repair the strands and cell death occurs
Is hypoxia a problem or a therapeutic opportunity?
Both.
Tumours that have a hypoxic region are not getting enough oxygen/proliferating, but are also not as susceptible to chemotherapy
This is a problem as radiotherapy requires oxygen
However, this can be boosted by using radiosensitive drugs or using hypoxia-selective drugs
How do radiosensitising drugs work?
Molecular oxygen is a potent radiosensitiser
Oxygen-mimetic radiosensitisers work in hypoxic cells by replacing oxygen in the chemical reactions that lead to DNA damage
E.g. Metronidazole and Etanidazole
Reduces glutathione concentration and inhibits glutathione S-transferase - tissues become more sensitive to ionising radiation
How do hypoxia selective drugs (pro-drugs) work?
- Five chemical moieties have the potential to be metabolised by enzymatic reduction under hypoxic conditions – nitro groups, quinones, aromatic and aliphatic N-oxides and transitions metals.
- Selectivity for hypoxic conditions relies on re-oxidation by oxygen of initial free radical intermediates formed by one-electron reduction of the prodrug. This means that in oxic cells the prodrug radical (more cytotoxic than the prodrug) is kept at low concentrations. This is not the case for hypoxic conditions.
- This inhibition of drug reduction by oxygen through the redox cycling was first shown in nitro compounds and shown to be responsible for the hypoxia-selective cytotoxicity of nitroimidazoles.
- Drug resistance increases in a tumour as the oxygen level decreases.
- Hypoxic region allows formation of reduced forms of pro-drug
How can telomeres be targeted in therapeutics (gen)?
Telomerases are able to keep on extending telomeres
G quadraplexes wrap themselves around and can be used to inhibit telomerase activity
if these could be stabilised - could prevent DNA replication
What could be some potential future targets in cancer chemo?
Potentiation of DNA-damaging therapies, exploitation of the abnormal physiology of solid tumours
Inhibition of angiogenesis
Interference with signalling, especially cell cycle control, and with management of DNA in the tumour cell
